This invention relates to novel intermediates and processes useful in the preparation of 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl)]-2,3,4,5 -tetrahydro-1H-pyrido[4,3-b]indole, also known as flutroline, a neuroleptic agent having valuable therapeutic activity, see Plattner et al., U.S. Pat. No. 4,001,263, and Harbert et al., J. Med. Chem. 23, pp. 635-643.
Plattner et al. and Harbert et al. also describe the earliest synthesis of flutroline: p-Fluorophenylhydrazine is condensed with N-carbethoxy-4-piperidone to form 8-fluoro-2-carbethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. By the Ulmann reaction the latter is arylated to form the 5-(p-fluorophenyl) derivative and then hydrolyzed under vigorous basic conditions to yield 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The synthesis of flutroline is completed by 2-alkylation with 3-(p-fluorobenzoyl)propyl chloride and finally reduction of the ketone group to an alcohol group.
Welch, U.S. Pat. No. 4,014,890 has described an alternative synthesis of the same earlier intermediate 8-fluoro-5-(p-fluorophenyl)-2-carbethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole, viz., by condensation of 1,1-di(p-fluorophenyl)hydrazine with N-carbethoxy-4-piperidone. In contrast to the present 2-carbobenzoxy intermediate, the earlier 2-carbethoxypyridoindole is a waxy solid difficult to isolate and purify by crystallization. Furthermore, in the further conversion to flutroline, the carbethoxy group must be removed under harsh, basic conditions, producing undesirable by-products which interfere with further processing (particularly by hydrogenation) and render difficult the isolation of flutroline in the highly purified form required for its use in therapy.
Welch, U.S. patent application, Ser. No. 334,195, filed Dec. 24, 1981 has described the preparation of flutroline by the reductive alkylation of 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (derived by the above earlier process) with the lactol, 2-(p-fluorophenyl)-5-hydroxytetrahydrofuran. Surprisingly, under hydrogenation conditions, the present carbobenzoxy derivative is converted more readily (milder conditions and/or more rapidly) to flutroline.
Welch, U.S. Pat. No. 4,267,331 has also described the preparation of related hexahydropyridoindole by reductive alkylation of 8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole . Murakami et al., Heterocycles 12, pp. 1571-1574 (1979) have described the preparation of unsymmetrical diarylhydrazines by reaction of aqueous sodium hypochlorite with unsymmetrical diarylureas in ethanol. Such hydrazines were condensed with pyruvate to form N-arylindole derivatives. In the present instance, Murkami's conditions failed to provide the required 1,1-di(p-fluorophenyl)hydrazine.
The present 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles are alternatively named as 1,2,3,4-tetrahydro-gamma-carbolines. In either case, the ring system is numbered as follows: ##STR1##